This invention is in the field of particles having an average diameter less than about 15 microns, and in particular is directed to methods and devices for making particles using the precipitation with compressed-fluid antisolvent (PCA) process and the carbon-dioxide assisted nebulization with a bubble dryer (CAN-BD) process.
Dry powder formulations with a controlled particle size and size distribution have many applications in the field of pharmaceutical drug delivery, especially in the areas of pulmonary delivery, controlled release, and needle-less powder injections. These formulations require precise control of particle size and size distribution. For example, pulmonary dosage forms of solid particles require particle diameters of about 1-3 μm in order to effectively target regions of the deep lung (J. Heyder et al. (1986) J. Aerosol Sci. 5:811). There has been considerable interest in developing polymeric nanoparticles (about 1-100 nm) that allow for targeted drug delivery to particular organs and tissues because they exhibit biodistribution profiles that are different from those of microparticles (greater than about 1 micron). For example, Desai et al. found the efficiency of uptake of 100 nm-sized poly (l-lactide-co-glycolide) particles by intestinal tissue was 15-250 fold higher compared to that for 1-10 μm sized particles (M. P. Desai et al (1996) Pharm. Res. 13:1838). Research in developing biodegradable polymeric nanoparticles has received attention because of their applications in controlled release formulations, as carriers for DNA in gene therapy, and their ability to deliver proteins, genes, and vaccines through a peroral route of administration (J. C Leurox, et al. (1996) J. Controlled Release 39:339; R. M. Kuntz, W. M. Saltzman, (1997) Trends Biotechnol, 15:364).
Traditional techniques for the production of micrometer and sub-micrometer particles include mechanical comminution (e.g., grinding and milling), recrystallization of solutes from solution using liquid antisolvents, double emulsion/evaporation processes, freeze drying and spray drying (B. Subramaniam, R. A. et al (1997) J. Pharm. Sci. 86:885). However these techniques have limitations that include excessive solvent use, thermal and chemical degradation of the solute, large residual solvent concentrations, and difficulties in controlling particle size and size distribution during processing. These limitations may affect powder stability, flow properties, and delivery efficiency (P. H. Hirst, et al. (2002) Pharm. Res. 19:258). Overall, the production of monodisperse powders with a controlled particle size in the micro/nanoscale remains challenging.
To address the shortcomings of traditional processing methods, supercritical fluid precipitation technologies that use supercritical carbon dioxide as an antisolvent have been investigated as a means for producing particulates. Supercritical fluids offer distinct advantages as antisolvents for precipitation. By adjusting both the temperature and pressure the physical properties of the supercritical fluid such as density, viscosity, and diffusivity can be readily varied. Favorable mass transfer characteristics, defined by a low viscosity and high diffusivity relative to liquids, offer the capability of producing monodisperse powders with low residual solvent concentrations. Supercritical carbon dioxide, by far the most common supercritical antisolvent, has a relatively low critical temperature (304.1 K) and pressure (7.38 MPa), low toxicity, and is inexpensive.
Precipitation with a compressed-fluid antisolvent (PCA) is a method that is capable of producing micrometer and sub-micrometer sized powders in a single-stage, scalable process. Under the conditions typically used in PCA processing, a solute is dissolved in an organic solvent and the resulting solution is injected into, or mixed with, a supercritical fluid antisolvent. Typically, the method involves the use of a particle formation chamber containing compressed fluid antisolvent. The operating temperature and pressure are selected so the supercritical fluid is completely miscible with the organic solvent. Due to the very rapid two-way mass transfer in supercritical fluid mixtures (i.e. solvent diffusing into the supercritical fluid and the supercritical fluid diffusing into the solvent) high degrees of supersaturation of the solute occur and the solute precipitates.
Past PCA research and development has focused on using jet hydrodynamics and liquid atomization theory as a guide for manipulating and controlling particle size during the PCA process. The Weber number, a ratio of inertial to surface tension forces, may be used to estimate droplet sizes in different atomization spray configurations (A. H. Lefebvre, Atomization and Sprays, Hemisphere Publishing Corp., Bristol, Pa., 1989). Liquid atomization theory predicts that larger Weber numbers will yield more intense atomization and hence smaller liquid droplet diameters. Smaller liquid droplets allow for an increase in the two-way mass transfer rates between the solvent/antisolvent, resulting in larger nucleation rates and smaller particles. With this theory as a guide, attempts have been made to control polymer particle size and size distribution (D. J. Dixon et al. (1993) AiChE J. 39:127; R. Bodemeier et al (1995) Pharm. Res. 12:1211; but only a weak variation in size with flow rate or Reynolds number was observed. In addition, various process parameters such as temperature, pressure, solute concentration, and solvent/solute flow rate have been manipulated to adjust particle size, but the results show there is a limited range in polymer size variation when these process parameters are varied. Overall, manipulation of particle size distributions has proved difficult using conventional PCA mixing configurations.
More recent research suggests that gaseous mixing theory and mixing rates, or rather, mixing length scales for turbulent mixing, should be used as a guide for manipulating and controlling particle size during the PCA process. Lengsfeld et al. (2000) J. Phys. Chem B, 104:2725) recently explored the validity of the assumption that liquid atomization controls the size of particles produced in the PCA process. They demonstrated that surface tension for jets of miscible fluids injected into critical and near-critical solvents is reduced to negligible levels over timescales shorter than the characteristic jet breakup time, and that distinct droplets never form. Studies by Werling et al. (J. O. Werling, P. G. Debenedetti (2000) J. Supercrit. Fluids 18:11) and Bristow et al. (2001) J. Supercrit. Fluids 21:257) also show that for supercritical conditions, where the solvent and antisolvent are completely miscible, there is no well-defined droplet interface that is stabilized by surface tension. Based on these results, liquid atomization theory and Weber number based analysis are no longer considered the appropriate theory and parameter to characterize the process. Instead, gaseous mixing theory and mixing rates, or rather, mixing length scales for turbulent mixing, should be used to characterize sprays of miscible fluids (B. Y. Shekunov et al. (1999) J. Crystal Growth 198/199:1345).
Various methods for mixing the solution and compressed antisolvent have been used. In one set of methods the solution is injected into a chamber of compressed antisolvent, and mixing between the two fluids occurs within the particle formation chamber. The solvent may be sprayed through a capillary tube (or capillary nozzle) directly into the chamber (Dixon et al. (1993), Materials, Interfaces, and Electrical Phenomena, 39(1), 127-139). Particle sizes obtained using this method are on the order of 0.1-5 microns. The solution may also be sprayed through a capillary tube onto a horn which is vibrated at ultrasonic frequencies. (Chattopadhyay and Gupta (2001), Ind. Eng. Chem. Res., 40, 3530-3539). In the later process, termed “SAS-EM”, mixing is carried out in the bulk of the particle formation chamber. The ultrasonic field generated by the horn surface is said to enhance turbulence and mixing within the supercritical phase, resulting in high mass transfer between the solution and the antisolvent and smaller particles (100-500 nm). The polydispersity of the particles reported was about 1.4 at a volume average particle size of 1100 nm and decreased to about 1.1 at a volume average particle size of 125 nm. However, the ultrasonic horns are expensive and have a limited life time at high pressure. Furthermore, heat is an unknown and uncontrolled variable. Heat may degrade molecules and affect the precipitation kinetics in the process as described. Furthermore, this process has not been demonstrated for polymer particles.
The solution may also be co-introduced with a flow of antisolvent into the chamber of compressed antisolvent. The flow of antisolvent generates additional mixing of antisolvent and solvent. Typically, the solution and antisolvent are introduced coaxially through a coaxial nozzle. The velocities of the two flows can be manipulated independently and the antisolvent flow velocity is typically greater than that of the solvent. (Mawson et al. (1997) 64, 2105-2118). The solution can also be co-introduced with a flow of antisolvent through ultrasonic spray nozzles (Falk et al., (1997), J. Controlled Release, 44, 77-85; Randolph, T. W. et al., (1993), Biotechnology Progress, 9, 429-435).
In some coaxial nozzle designs, mixing between the solution and the antisolvent does not occur within the nozzle. For example, Mawson et al. (1997, supra) show a coaxial nozzle having an inner nozzle tube which extends beyond an outer nozzle tube. The inner tube carries the solvent while the outer tube carries the antisolvent.
Other coaxial nozzle designs do provide some mixing of the solution and the antisolvent within the nozzle. U.S. Pat. No. 5,851,453 to Hanna et al., issued Dec. 22, 1998 describes a coaxial nozzle in which the outer nozzle passage extends beyond the inner nozzle passage. The ends of both nozzle passages are tapered. In this configuration some mixing of the solvent and antisolvent can occur within the nozzle before the fluids pass into the main chamber of the PCA apparatus. The mean particle sizes demonstrated are greater than one micron. Yu et al. ((2001), Chem. Eng. Sci., 56, 2421-2433) describe a coaxial nozzle consisting of two tubes (for internal solution and external CO2 flows) opening into a small premixing chamber. Although Yu et al. (2001) show a decrease in the mean particle diameter with an increase in the Reynolds number, the particles are not nanosized. Instead, the smallest mean particle diameter discussed appears to be about 5 microns in diameter. The size distribution of the particles does not appear to be reported, but the SEM photos of the smaller particles show clear size differences. The authors state that large-scale inhomogeneity may still exist in the flow through the nozzle.
Another type of nozzle design for co-introduction of antisolvent and solution mixes two antisolvent flows and a solution within a chamber inside the nozzle (WO 98/35825, Hanna and York, published Aug. 27, 1998). In one embodiment, the nozzle provides a first fluid inlet means for the introduction into the chamber of a first supercritical fluid and a solution and second fluid inlet means for introducing simultaneously an impinging flow of the second supercritical fluid at an angle to, and directed at, the direction of flow of the first supercritical fluid. In a “cross-flow” nozzle, the two supercritical fluids were opposing (angle between the supercritical fluids of 180°). The first inlet means preferably has two or more concentric passages through which may be introduced a flow of the first supercritical fluid and a flow of the solution (i.e. the first inlet means preferably is a coaxial nozzle). Nozzle configurations are also described in which the solution is introduced at an angle to the flow of the first supercritical fluid, so long as it is then dispersed by the supercritical fluid(s) immediately as it comes into contact with them. In particular, a configuration is shown where the solution is introduced perpendicular to that of two countercurrent supercritical fluid flows. A cross-flow nozzle was demonstrated to produce particles in the size range 200-750 nm for a variety of materials. For nicotinic acid, it was claimed that the size distribution of (particles was narrowed compared to particles produced with a conventional coaxial nozzle.
Carbon Dioxide-Assisted Nebulization with a Bubble Dryer (CAN-BD) is another particle formation method that is capable of producing powders less than about 6.5 microns in diameter. Under the conditions typically used in CAN-BD processing, a solute is dissolved in an aqueous solvent and the resulting solution is mixed with a supercritical fluid. In contrast to the PCA process, in the CAN-BD process the solvent is either insoluble or partially soluble in the supercritical fluid and the supercritical fluid is partially soluble in the aqueous solvent. The particles are formed through rapidly expanding the mixture into a region in which the temperature and pressure are below the critical temperature and pressure of the supercritical fluid. The rapid decompression of the supercritical fluid, coupled with the explosive release of dissolved supercritical fluid in the aqueous solution, acts to atomize the aqueous solution and produce an aerosol. This aerosol is directed into a stream of co-flowing heated gas (typically air or nitrogen), and particle formation results due to evaporation of the solvent. Solvent evaporation from droplets occurs in a plume that extends from the injection nozzle. The length of this plume is important for equipment design, as the plume must not impinge on any surfaces or vessel walls before evaporation is complete, or else severe agglomeration of wet particles may result. The size of this plume may be minimized by efficiently mixing the supercritical fluid with the aqueous solvent in a fashion so that the concentration of supercritical fluid dissolved in the aqueous phase immediately before expansion into the drying chamber is as high as possible. Sievers et al. (U.S. Pat. No. 5,639,441, issued Jun. 17, 1997) discloses a mixing tee with a dead volume less than about 10 μl for mixing the supercritical fluid and solvent.
There remains a need in the art for improved methods and devices for producing particles with an average diameter less than 15 microns, preferably particles with an average diameter less than 1 micron. Furthermore, there remains a need in the art for particles with a controlled particle size. Preferably the particles have a narrow size distribution, with a polydispersity less than about 1.75. Although nanoscale particles have been made using the PCA and CAN-BD processes, the resulting particle size distributions have not always been optimal.